The present invention relates to a TRPA1 activity inhibitor, more precisely isopentenyl pyrophosphate, a compound for suppressing TRPA1 mediated pain by inhibiting TRPA1 activity and a novel use of the same.
TRPA1 (transient receptor potential cation channel, subfamily A, member 1) was first found in 2003 owing to the studies in the fields of human physiology and pharmacology. TRPA1 is activated as it recognizes diverse stimuli such as low temperature stimulus, inflammatory stimulus, and mechanical stimulus, etc. And by the activation of TRPA1, the human body feels pain. TRPA1 belongs to thermoTRP family (temperature-sensitive transient receptor potential ion channels) that is the pain receptor family recognizing temperature and painful stimuli. Researches expect that human pain recognition mechanism can be explained by disclosing functions of TRPA1, the pain receptor, and additionally the pursuing goal of pain relief can be achieved by the development of a TRPA1 regulator.
There is no report on an endogenous pain inhibitor, yet. Studies have been actively going on different types of pain, but mechanisms of pain regulators in vivo have not been disclosed yet. Prostaglandin generated by inflammation and its metabolites and aldehydes are known as pain inducing materials.
To understand basic techniques used for the development of a pain inhibitor based on the TRPA1 specific inhibitor, it is important to understand the characteristics of TRPA1. TRPA1 is an ion channel and its activation makes cations migrate into sensory neurons, changing of cell membrane currents. The changes of cell membrane currents result in the generation of active potential, which is at last transferred to the brain to recognize pain. One of the techniques to measure TRPA1 activation is patch-clamp electrophysiological technique measuring the changes of membrane currents after amplifying thereof. And another technique to measure TRPA1 activation is to measure intracellular calcium level based on the fact that TRPA1 is involved in the migration of cations such as calcium ions. The first technique is superior in sensitivity to the second one, but the second technique is superior in high speed to the first one, so that they are complementary to each other. Such techniques to measure TRPA1 activation can be executed by the support of animal neuron culture technique, cell line culture technique, TRPA1 DNA control and transfection techniques. Various TRPA1 specific inhibitor candidates and a standard activator are administered to TRPA1 over-expressing cells and then inhibiting effect of TRPA1 activation therein is measured to select a proper TRPA1 inhibitor and determine its capacity.
The present inventors constructed a cell line expressing TRPA1 and treated the cell line with isopentenyl pyrophosphate and cinnamaldehyde known as a TRPA1 activator. Then, responses therein were compared. At last the present inventors completed this invention by confirming that isopentenyl pyrophosphate inhibited TRPA1 activity and thus it could be effectively used as an inhibitor of TRPA1 mediated pain.